This program project application brings together a strong multidisciplinary team to study key issues in the virology and immunology of HIV transmission, early pathogenesis, and superinfection during early HIV. The Clinical Core will provide a central resource for the proposed projects by recruiting and following persons with acute and early HIV. A unique resource will be enrollment of potential source partners who transmitted HIV. The Clinical Core will be based on an acute/early HIV program that has a strong track record of recruiting persons with acute/early HIV as well as identifying their source partners. Four closely integrated studies are planned: Project 1 (Hecht PI) will examine the transmission of cytotoxic T-lymphocyte (CTL) escape and drug resistance mutations and their persistence after transmission. It will test the hypotheses that there are not substantial barriers to transmission of drug resistant and CTL escape variants present in source partners, and that differences in viral fitness will predict time to emergence of wild type virus in persons with primary drug resistance or CTL escape mutations. Project 2 (Deeks PI) will examine the evolution of HIV env properties (tropism, ability to cell-to-cell fusion, and susceptibility to neutralizing antibodies [NAb]) during transmission from source to spread partner and evolution following transmission. This project will test the hypotheses that in early infection HIV will tend to be less fusogenic to escape neutralizing antibodies, while the loss of ability to evolve NAb to HIV will allow more fusogenic virus to emerge, and that fusogenicity will be an important predictor of rate of CD4+ T-cell loss. Project 3 (Grant PI) will prospectively follow participants over the first years following HIV infection to better determine the risk of superinfection by time since infection and virologic and humoral immune predictors of susceptibility to superinfection. Project 4 (Nixon PI) will examine the role of HIV specific T-cell responses in driving reversion of CTL escape mutations acquired during HIV transmission to a partner with a different HLA type and the role of CTL responses in superinfection. The Administrative and Analysis Core will provide scientific leadership and data management and statistical support. The overarching aims of this project are to advance our understanding of the immunologic and virologic factors that reduce the vulnerability of individuals to superinfection in the first 2-3 years of infection, and to better understand the evolution of HIV as it adapts to a new host environment following transmission. This will provide critical insights into the development of protective immunity following HIV infection, and into the evolution and pathogenesis of HIV in early infection.